The carbostyril derivatives represented by the above general formula (I) and the processes for producting thereof are described in Japanese Patent Publication No. 35623/1988. Further, the usefulness of the carbostyril derivative as an anti-gastric ulcer agent is described in Japanese Patent Application Kokai (Laid-Open) No. 74329/1991.
Also the usefulness of these carbostyril derivatives as an agent for curing diabetes is described in International Publication No. WO 92/21342; their usefulness as an agent for protecting intestinal mucosa from disorders is described in International Publication No. WO 94/12182; and their usefulness as an agent for inhibiting reduction in somatostatin secretion is described in International Publication No. WO 93/24043.
Interleukin-8 (hereinafter abbreviated to IL-8), which is also called a neutrophil leucocytes-activating factor, is a basic heparin binding polypeptide composed of 72 amino acids and is a cytokine produced not only from activated macrophages but also from various types of human cells.
IL-8 has various physiological activities such as the followings. (1) IL-8 is a chemotactic factor to neutrophil leucocytes, T cells and basophil leucocytes; (2) IL-8 activates neutrophil leucocytes, releases a lysosomal enzyme, changes the adhesion of neutrophil leucocytes to the endothelial cells of blood cells, and exasperates the inhibitory effect for propagation of candida species; (3) IL-8, when injected into joints, gives rise to destruction of synovial membrane accompanied with wetting of a large amount of neutrophil leucocytes; (4) IL-8 increases the appearance of adhesion factor on the surface of neutrophil leucocytes; (5) IL-8 controls the release of histamine from basophil leucocytes; and (6) IL-8 activates neutrophil leucocytes in artificial organs. IL-8 is also called as an inflammatory cytokine, and abnormal production of IL-8 and excessive reaction to IL-8 are thought to cause inflammatory diseases.
Behcet disease is a peculiar systemic inflammatory disease which attacks the mucous membrane of oral cavity, eyes, pudenda, skin and nearly all organs. The cause of the disease is said to be connected with infection, immunological abnormality, etc. but is not clarified yet. In curing the disease, there are used steroidal hormones, colchicine, Endoxan, cyclosporins, etc., but they must be used with the greatest possible care in view of their side effects. No useful curing agent has been found yet which is safe and can be administered over a long period.
The aphthous stomatitis caused by diseases such as stomatitis and the like is difficult to clinically distinguish from the aphthous stomatitis caused by Behcet disease and, similarly to Behcet disease, is intractable and recur often. In curing the disease, nosotropic therapies such as local administration of steroidal hormones, coating of silver nitrate, and the like are applied because the cause of stomatitis is unclear in many cases. In these therapies, however, continuous application is difficult because of, for example, the side effect of the substance used and, when the therapy is stopped, there is often seen recurrence of the disease. No useful curing agent has been found yet which is safe and can be administered over a long period. Stomatitis often shows an ulcerative symptom but there is no report mentioning that any anti-gastric ulcer agent is useful for such stomatitis.
Nephritis is thought to be caused not only by infection and an immunological mechanism but also by a nonimmunological mechanism. When nephritis is caused, for example, by various other diseases such as serum coagulation system disease, fibrinolytic system disease, hypertension and the like, it is said that nephritis is also induced by the quality of meal, etc. Thus, nephritis is a very complicated disease and is very difficult to cure. Hence, many researches are under way in order to find out an effective method for curing nephritis.
Curing of nephritis has hitherto been conducted by administering various drugs such as steroidal drug, immunosuppressive agent, non-steroidal anti-inflammatory agent, anticoagulant, antithrombocyte agent and the like. However, the steroidal drug shows a side effect when administered in a large amount over a long period; the immunosuppressive agent, showing a more striking side effect, must be used and applied with sufficient care; and the anticoagulant and the antithrombocyte agent are merely for alleviating the condition of nephritis and do not cure the root cause of the disease.
Hence, it is desired that the mechanism of nephritis development is clarified fully, that a reasonable method for curing nephritis is established and that a drug is developed which is effective for nephritis and which can be used safely over a long period.
In recent years, there has often been seen a case in which the excessive utterance required in special occupations owing to the change in social needs causes chorditis and consequent voice disorders. In such a case, since the excessive utterance is forced for occupational reasons, the voice disorders cannot be cured by silence cure, etc. when the patient is unable to fe freed from work. As a result, the vocal cord having inflammation is used excessively and it is often difficult to improve the voice disorders by an ordinary conservative cure alone. Hence, various researches are under way on a drug suitably used for cure of voice disorders. The methods currently used for curing voice disorders include spraying the throat with a vasoconstrictor or an adrenocortical hormone (this is an supplementary method), but the spraying method has a safety problem when continuously used over a long period. It is therefore desired to develop a drug which is low in side effect and which can be used safely over a long period.